Treatment of rats with fentrazamide for 2 years at 3000 ppm (males) and 4000 ppm (females) led to an increased incidence and degree of axonal degeneration in sciatic nerve as well as to effects on red blood cells. The mechanism underlying these effects was investigated in vitro using various cell cultures (permanent rodent cell lines from the nervous system, liver, kidney, skeletal and heart muscle and fibroblasts, primary cortical neurons and erythrocytes from the rat). Added to cultured rat cortical neurons for 1 week, fentrazamide considerably decreased glucose consumption, ATP levels and mitochondrial membrane potential and lowered the GSH level, however, it had little impact on viability and neurofilaments and did not induce oxidative stress (ROS) over the first 2 h. After recovery for 1 week, in addition some destruction of neurofilaments had occurred probably secondary to the disturbance of energy production. These effects were prevented by pyruvate. Further studies indicated that fentrazamide primarily inhibited glucose utilization, most likely by interfering with glycolysis. Similar effects were found in erythrocytes treated with fentrazamide over a period of 7 days. Primarily, the glucose consumption was reduced after 1-day treatment, followed by a marked reduction of the energy supply at days 3 and 7. Comparable to the neurons, the GSH level was significantly reduced. A marked hemolysis of the red blood cells was then observed after prolonged treatment. The extensive energy demand and exclusive dependency on glucose utilization of neurons and erythrocytes may explain the specific vulnerability of motor neurons and erythrocytes. When comparing the concentrations necessary for inducing effects in vitro on neuronal cells and erythrocytes to the very low plasma concentrations of fentrazamide in treated rats it is suggested that only a small impact of fentrazamide on the energy status at high doses will occur in vivo. Therefore, aging of the rat as another factor compromising mitochondrial energy production in motor neurons must be considered as additional contribution for the induction of axonal degeneration. It is concluded that this effect of fentrazamide in rats poses no specific risk under the exposure conditions relevant to humans.

中文翻译：

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新型除草剂芬沙酰胺对体外神经元和红细胞葡萄糖利用的影响。

用苯达草酰胺在3000 ppm（雄性）和4000 ppm（雌性）下治疗大鼠2年，导致坐骨神经轴突变性的发生率和程度增加，并对红细胞产生影响。使用多种细胞培养物（来自神经系统的永久啮齿动物细胞系，肝脏，肾脏，骨骼和心脏肌肉以及成纤维细胞，大鼠的原代皮层神经元和红细胞）在体外研究了这些作用的潜在机制。在培养的大鼠皮质神经元中添加1周后，芬太尼酰胺可显着降低葡萄糖消耗，ATP水平和线粒体膜电位，并降低GSH水平，但是，对活力和神经丝几乎没有影响，并且在最初的第一个实验中不会引起氧化应激（ROS） 2小时 恢复1周后，另外，可能由于能量产生的干扰而发生了一些神经丝的破坏。丙酮酸阻止了这些作用。进一步的研究表明，芬太尼酰胺主要抑制葡萄糖的利用，最可能是通过干扰糖酵解来实现的。在7天的时间里，使用Fentrazamide处理的红细胞发现了类似的效果。首先，经过1天的治疗，葡萄糖的消耗量减少了，随后在第3天和第7天，能量的供应显着减少了。与神经元相比，GSH的水平明显降低了。长时间治疗后，观察到红细胞明显溶血。大量的能量需求和对神经元和红细胞葡萄糖利用的完全依赖可能解释了运动神经元和红细胞的特殊脆弱性。当比较在治疗大鼠中体外诱导神经元细胞和红细胞诱导作用所需的浓度与极低的芬沙酰胺血浆浓度时，建议在体内高剂量的芬沙酰胺对能量状态只会产生很小的影响。因此，必须将大鼠衰老作为损害运动神经元中线粒体能量产生的另一个因素，作为诱导轴突变性的额外贡献。结论是，在与人类有关的暴露条件下，芬太拉amide对大鼠的这种作用没有特别的危险。